The objective of this program is to develop information at the molecular level which may ultimately be useful in reducing MTX toxicity to the intestine or in providing sensitive methods for the early detection of gastrointestinal malignancies. The following specific projects are to be undertaken: (1) Study of the interaction of MTX with purified intestinal dihydrofolate reductase; (2) Study of the mechanism by which MTX and other folate compounds are transported across the intestine; (3) The development of procedures for reducing MTX toxicity in the intestine; and (4) A comparative study of the properties of dihydrofolate reductase and thymidylate synthetase from normal intestinal epithelium as contrasted with malignant intestinal tumors. This comparative information may serve as an aid in the differential diagnosis of malignant disease.